Document text
Principal Investigator: Michael Simons
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $645,489
Funding agency: National Heart Lung and Blood Institute
Project Summary
Uncontrolled inflammation is a key driver of acute and chronic cardiovascular pathology.
However, the accompanying edema, one of the four cardinal signs of inflammation defined by
Celsus and Galen two millennia ago, is poorly understood and often ignored at the mechanistic
level. Yet ample evidence shows its causal roles in ischemia reperfusion injury (IRI) and
resultant sequelae in the heart, brain, and other organs.
While a number of molecules can induce edema formation, vascular endothelial growth factor
(VEGF), also known as vascular permeability factor (VPF) has been viewed as the key
component of IRI-associated edema development. There are a number of drugs capable of
blocking VEGF signaling, including vascular permeability that are widely used as anti-
angiogenic cancer and ophthalmologic drugs such as bevacizumab, sorafenib, sunitinib and
pazopanib among others. However, none of them can be used in acute/chronic ischemia
settings due to the induced loss of blood vasculature.
Exciting new data from our lab have demonstrated that it is possible to selectively block VEGF-
induced permeability defects without affecting other aspects of its signaling, thereby eliminating
anti-angiogenic effects of non-selective anti-VEGF therapies. In preliminary studies, blocking
VEGF-blocking edema formation leads to a ~50% reduction in the size of myocardial infarction
and preservation of LV systolic and diastolic function and suppression of VT inducibility. With
these preliminary results in hand, we propose to examine the functional effects myocardial
edema and evaluate the effect of anti-edema therapies in this setting.
Terms: <7B4 Antigen><7B4 protein><7S Gamma Globulin><Acute><Acute myocardial infarct><Acute myocardial infarction><Adherence><Affect><Affinity><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Inhibitors><Angiostatic Agents><Animal Model><Animal Models and Related Studies><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Anti-VEGF><Anti-VEGF Humanized Monoclonal Antibody><Anti-VEGF RhuMAb><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Arrhythmia><BAY 54-9085><Binding><Biological><Bleeding><Blocking Antibodies><Blood flow><Brain><Brain Nervous System><CD144 Antigen><Cancers><Cardiac Arrhythmia><Cardiac Output><Cardiac infarction><Cardiovascular Pathology><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Chronic><Chronic Phase><Clinical Treatment Moab><Coronary><Data><Defect><Dephosphorylation><Development><Dropsy><Drugs><ECM><Edema><Electrophysiology><Electrophysiology (science)><Encephalon><Endothelial Cells><Endothelium><Epidemic><Event><Extracellular Matrix><FLK1><Fibrosis><GEM model><GEMM model><Genetically Engineered Mouse><Goals><Hand><Heart><Heart Arrhythmias><Heart Injuries><Heart failure><Hemorrhage><Hu-mABs><Human><Hydrops><Hypokalemia><Hypopotassemia><IgG><Immunoglobulin G><Incidence><Infarction><Inflammation><Inflammatory><Injury><Intracellular Communication and Signaling><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><KDR gene><Kinetics><Knock-out><Knockout><Lead><Left Ventricular Dysfunction><Link><Liquid substance><Lymphatic function><Maintenance><Malignant Neoplasms><Malignant Tumor><Medication><Membrane><Mice><Mice Mammals><MoAb VEGF><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Monoclonal Antibody Anti-VEGF><Murine><Mus><Myocardial><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardial Ischemic Reperfusion Injury><Myocardial Reperfusion Injury><Myocardial depression><Myocardial dysfunction><Neovascularization Inhibitors><Neurophysiology / Electrophysiology><Organ><Outcome><Pathogenesis><Pb element><Permeability><Pharmaceutical Preparations><Phenotype><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Production><Protein Dephosphorylation><Protein Phosphorylation><Public Health><Receptor Protein><Recombinant Humanized Anti-VEGF Monoclonal Antibody><Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor><Recovery of Function><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><RhuMAb VEGF><Role><Safety><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Site><Sorafenib><Structure><Therapeutic><Time><Translating><Translations><VE-Cadherin><VEGF><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VEGFs><VPF Receptor><Validation><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Endothelial Growth Factors><Vascular Permeabilities><Vascular Permeability Factor Receptor><Ventricular Arrhythmia><Ventricular Tachycardia><Wound Repair><X-ray microtomography><Xray microtomography><acute cerebrovascular accident><acute stroke><antiangiogenic><bevacizumab><biologic><biological signal transduction><blocking factor><blood loss><cadherin 5><cardiac dysfunction><cardiac failure><cardiac function><cardiac infarct><cardiac injury><cardiac ischemia><coronary attack><coronary infarct><coronary infarction><coronary ischemia><developmental><drug/agent><electrophysiological><fibroglycan><fluid><function of the heart><functional recovery><genetically engineered mouse model><genetically engineered murine model><hands><heart attack><heart dysfunction><heart function><heart infarct><heart infarct sizing><heart infarction><heart infarction sizing><heart ischemia><heart output><heavy metal Pb><heavy metal lead><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><improved><in vivo><infarct><injuries><interstitial><left ventricle abnormality><liquid><mAbs><malignancy><membrane structure><micro CT><micro computed tomography><microCT><microtomography><model of animal><monoclonal Abs><mutant><myocardial infarct sizing><myocardial infarction sizing><myocardial ischemia/hypoxia><myocardium ischemia><neoplasm/cancer><new approaches><novel><novel approaches><novel strategies><novel strategy><pre-clinical><preclinical><preservation><prevent><preventing><receptor><reperfusion><response><rhuMabVEGF><social role><sudden cardiac death><syndecan-2><systemic inflammation><systemic inflammatory response><translation><validations><vascular endothelium permeability><wound healing><wound injury><wound recovery><wound resolution>